Primary focal segmental glomerulosclerosis (FSGS) is an organ-specific autoimmune disease with poor response to immunomodulating agents and a poor prognosis. The relatively small number of children and young adults with FSGS and the lack of compelling prospective double-blind randomized multi-center therapeutic studies have hampered the formulation of an evidenced-based therapeutic approach. Cyclophosphamide and calcineurin inhibitors act on different sites of the cytotoxic T cell cycle and support the hypothesis of synergistic effectiveness of combination therapy. We propose a double-blind, randomized, controlled trial comparing A) sequential cyclophosphamide followed by tacrolimus with oral steroids and angiotensin-converting enzyme inhibitors (ACEI) with B) tacrolimus with oral steroids and ACEI. We will develop a database to compare the response to each treatment arm with respect to the primary end-point: reduction in proteinuria. The secondary outcomes will be remission rate, relapse frequency, progression of renal failure as measured by glomerular filtration rate, total cumulative corticosteroid dose and adverse events. Patient age, ethnicity, gender, renal histological classification, podocin mutation status, baseline proteinuria and baseline renal excretory function will be correlated with primary and secondary outcomes. We have formed a Western Pediatric Nephrology Clinical Trials Group consisting of 28 pediatric centers with collaborating adult nephrologists. These centers have a rich history of successful collaborative studies in the past. From our initial survey of patients in the past two years, we have a more than sufficient patient population-base from which to recruit to ensure enrollment of at least 100 study subjects in our region. We will participate as a regional center in the collaborative, multicenter randomized controlled clinical trial of therapy to improve the clinical course of children and young adults with primary FSGS as stated in the RFA.